tbuckley/cabot-search huggingface dataset:
Abstract 1487: Role of micro-RNA199a-3p in lymph node stromal extracellular vesicles on tumorigenesis in colorectal cancer
Authors: Hallie Baer, Jessica Simon, Lara McKean-Baste, Alicia N. Ray, Heather Green, Grace Maresh, Xin Zhang, David Marjolin, Jennifer Paruch, Li Li
Journal: Cancer Research (2022)

Abstract Introduction: MicroRNAs (miRNAs) are short non-coding RNAs implicated in post-transcriptional regulation of gene expression. Abnormal expression of miRNAs in cancer is associated with enhanced tumorigenesis and metastatic potential. Our previous data has shown that extracellular vesicles (EV) secreted by human lymph node stromal cells (LNSC) enhance tumorigenesis in colorectal cancer (CRC). By systemic searching and modifying miRNAs carried by EV through overexpression and inhibition on LNSC, we aim to demonstrate their effect on CRC progression in vitro and orthotopic mouse model. Methods: Total microRNA sequencing was analyzed using in-silico computer prediction models. Four overexpressed miRNAs in the LNSC-EV were selected (miR-155-5p, miR-199a-3p, mi-143-3p, and mi-214-3p). Tumor cell proliferation assay was performed using a CRC SW620 cell line transfected with selected miRNA mimics or inhibitors or controls. In our mouse model, miRNA transfected SW620 cells tagged with luciferase/RFP, were injected into the rectal submucosa of NOD/SCID mice. Tumor growth and metastases were observed by weekly bioluminescent imaging (BLI). At week 7, tumors were weighed and BLI of the tumors and organs were recorded. Immunohistochemistry staining was performed on the paraffin sections of tumors, livers and lung collected from these mice. Results: In vitro proliferation assays, cells transfected with the mimic of miRNA 199a-3p significantly increased CRC SW620 cell proliferation (p&amp;lt;0.01) while cells treated with the inhibitor showed decreased proliferation (p&amp;lt;0.05). In our orthotopic mouse model, mice with SW620 cells transfected with the mimic had increased frequencies of tumorigenesis (94% vs. 14%) and liver and lung metastasis comparing to control group (56% vs 9.5%, 50% vs 0%). Mice injected with SW620 cells transfected with the miRNA inhibitor had decreased tumor growth compared to the negative control (p&amp;lt;0.05). Conclusion: Our study shows that miRNAs carried in LNSC-EV are crucial for CRC progression. Specifically, inhibition of miRNA-199a-3p may serve as a therapeutic target in the treatment of CRC. Understanding the role and mechanisms of this miRNA in CRC could lead to the improved management of patients with CRC. Citation Format: Hallie Baer, Jessica Simon, Lara McKean-Baste, Alicia N. Ray, Heather Green, Grace Maresh, Xin Zhang, David Marjolin, Jennifer Paruch, Li Li. Role of micro-RNA199a-3p in lymph node stromal extracellular vesicles on tumorigenesis in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1487.
Quality of life in patients with central centrifugal cicatricial alopecia: a preliminary study
Authors: Abena Maranga, Fritzlaine C. Roche, Maryam Alausa, Tara McWilliams, David J. Margolis, Gabriella Fabbrocini, Carlo Natale Lauro, Rosanna Cataldo, Susan C. Taylor
Journal: British Journal of Dermatology (2022)

Central centrifugal cicatricial alopecia (CCCA) is a common cause of hair loss among patients of African and/or Caribbean descent, and there is little data exploring the quality of life of patients with this condition. This pilot demonstrates that CCCA has a significant impact on overall quality of life, and patients may benefit from resources to address psychosocial aspects of this diagnosis.
Abstract 6175: Developing antibody-drug conjugates against cholangiocarcinoma using a novel molecular target
Authors: Bing Zhu, Shi-Li Yao, Xin-Yan Wang, Rui Xu, Peng Guo, Jie-Er Ying
Journal: Cancer Research (2022)

Abstract As a rare malignancy, cholangiocarcinoma (CCA) is a lethal disease with a 5-year overall survival rate of merely 5%. Highly invasive and asymptomatic characteristics of CCA cause most patients diagnosed at advanced stages, severely deteriorating their clinical outcomes. The drug treatment options for CCA are limited and surgical resection of CCA frequently suffers from a high recurrence rate of 66%. Albeit Pemigatinib, a FGFR2 inhibitor, has recently been approved by FDA as the first CCA-targeted therapeutic, only less than 10% of patients with CCA carry FGFR2 fusion mutations that can benefit from this drug. Ivosidenib, another targeted drug against IDH1 mutation, only works for 13% CCA patients carrying this mutation. Therefore, discovering new molecular targets and developing associated targeted drugs remain a significant and unmet medical need in CCA therapy. In this study, we first screened potential molecular targets for CCA by comparing the expression levels of a panel of cancer-related cell membrane antigens between human CCA cells and normal human intrahepatic biliary epithelial cells through flow cytometry. CD54 was identified as a remarkable molecular target of CCA with strong binding force to its antibodies and high endocytosis efficiency by flow cytometry and confocal fluorescent microscopy. Meanwhile, we confirmed that CD54 was absent in most normal human tissues but was highly upregulated in CCA tumor tissues through immunohistochemical (IHC) staining. Based on this newly discovered CCA target, we constructed a series of CD54 antibody-drug conjugates (ADCs) using different chemical linkers and payloads. We next evaluated and compared the half maximum inhibitory concentrations (IC50s) of each ADC in ablating human CCA cells in vitro in order to identify an optimized ADC formulation. Furthermore, we validated its anti-tumor efficacy against primary and peritoneal metastatic CCA tumors in vivo in comparison with conventional chemotherapy. Eventually, we determined the biodistribution and safety profile of this CD54 ADC in order to ensure that it is well-tolerated under the effective dose. In general, we identified CD54 as a novel molecular target for CCA through antibody library screening, and explored its potential in the development of CCA-targeted ADCs, providing a promising targeted therapeutic for clinical treatment of CCA. Citation Format: Bing Zhu, Shi-Li Yao, Xin-Yan Wang, Rui Xu, Peng Guo, Jie-Er Ying. Developing antibody-drug conjugates against cholangiocarcinoma using a novel molecular target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6175.
Abstract 5674: A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis
Authors: Li Fan, Qingfei Pan, Wentao Yang, Selene C. Koo, Cheng Tian, Liyuan Li, Meifen Lu, Anthony Brown, Bensheng Ju, John Easton, Sarangarajan Ranganathan, Soona Shin, Alexander Bondoc, Jun J. Yang, Jiyang Yu, Liqin Zhu
Journal: Cancer Research (2022)

Abstract Background and Rationale: Hepatoblastoma (HB) is the most common pediatric liver cancer. Its predominant occurrence in very young children led us to investigating whether the neonatal liver provides a protumorigenic niche to HB development. Methods: HB development was compared between orthotopic transplantation models established in postnatal day 5 and 60 mice (P5Tx and P60Tx models). Single-cell RNA-sequencing was performed using tumor and liver tissues from both models and the top candidate cell types and genes identified are investigated for their roles in HB cell growth, migration, and survival. Results: We found that various HB cell lines including HepG2 cells were consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models revealed that the P5Tx tumor was more hypoxic and had a larger number of activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver which express significantly higher levels of Cxcl1 than those from the P60Tx model. We found these differences were developmentally present in normal P5 and P60 liver. We showed that the Cxcl1/Cxcr2 axis mediated HB cell migration and was critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induced intrahepatic and pulmonary metastasis and CXCR2 knockout in HepG2 cells abolished their metastatic potential in the P5Tx model. Lastly, we showed that in metastatic HB patient tumors there was a similar larger population of aHSCs in the tumor-surrounding liver than in localized tumors, and tumor hypoxia was uniquely associated with HB patient prognosis among pediatric cancers. Conclusion: We demonstrated that the neonatal liver provides a prometastatic niche to HB development via the Cxcl1/Cxcr2 axis. Citation Format: Li Fan, Qingfei Pan, Wentao Yang, Selene C. Koo, Cheng Tian, Liyuan Li, Meifen Lu, Anthony Brown, Bensheng Ju, John Easton, Sarangarajan Ranganathan, Soona Shin, Alexander Bondoc, Jun J. Yang, Jiyang Yu, Liqin Zhu. A developmentally prometastatic niche to hepatoblastoma in neonatal liver mediated by the Cxcl1/Cxcr2 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5674.
Case 24-2022: A 31-Year-Old Man with Perianal and Penile Ulcers, Rectal Pain, and Rash
Authors: Nesli Basgoz, Catherine M. Brown, Sandra C. Smole, Lawrence C. Madoff, Paul D. Biddinger, Joshua J. Baugh, Erica S. Shenoy
Journal: New England Journal of Medicine (2022)
SCADIE: simultaneous estimation of cell type proportions and cell type-specific gene expressions using SCAD-based iterative estimating procedure
Authors: Daiwei Tang, Seyoung Park, Hongyu Zhao
Journal: Genome biology (2022)

Abstract A challenge in bulk gene differential expression analysis is to differentiate changes due to cell type-specific gene expression and cell type proportions. SCADIE is an iterative algorithm that simultaneously estimates cell type-specific gene expression profiles and cell type proportions, and performs cell type-specific differential expression analysis at the group level. Through its unique penalty and objective function, SCADIE more accurately identifies cell type-specific differentially expressed genes than existing methods, including those that may be missed from single cell RNA-Seq data. SCADIE has robust performance with respect to the choice of deconvolution methods and the sources and quality of input data.
Examining the interrelationships between mindfulness‐based interventions, depression, inflammation, and cancer survival
Authors: Debra A. Marinovic, Rebecca L. Hunter
Journal: CA A Cancer Journal for Clinicians (2022)

Depression is highly prevalent in those diagnosed with cancer and is also associated with poorer prognostic outcomes. Mindfulness-based interventions are effective in reducing depressive symptoms and improving quality of life in patients with cancer. The objective of this review was to investigate whether mindfulness practices can improve survival and, if so, what mechanisms of action may contribute to these outcomes. Although no long-term studies have investigated this hypothesis, the current literature supports an inflammatory basis for depression, implicating proinflammatory cytokines and hypothalamic-pituitary-adrenal axis dysfunction as contributing factors. Markers of inflammation, such as interleukin-6, tumor necrosis factor-α, and cortisol, are all found at elevated concentrations in many depressed individuals. These exact mechanisms are associated with higher mortality in patients with cancer. Mindfulness has been studied for its effects on cytokine and cortisol levels, and there are promising data to support that the intervention can measurably decrease inflammation. Therefore, it is conceivable that mindfulness programs can affect survival in this population. There are limited data on the long-term effects of mindfulness on depression and inflammatory markers in patients with cancer, and there are potential barriers to the implementation of mindfulness-based interventions as part of a comprehensive treatment plan. Therefore, it is necessary to further explore these questions through longitudinal studies to establish a survival correlation. CA Cancer J Clin. 2022;72:490-502.
Abstract 2651: The tankyrase inhibitor OM-153 demonstrates anti-tumor effect with a therapeutic index above 10
Authors: Shoshy Alam Brinch, Enya Amundsen-Isaksen, Sandra Espada, Aleksandra Aizenshtadt, Lone Holmen, Clara Hammarström, Merete Høyem, Hanne Scholz, Gunnveig Grødeland, Sven T. Sowa, Albert Galera-Prat, Lari Lehtiö, Ilonka A.T.M. Meerts, Ruben G. G. Leenders, Anita Wegert, Stefan Krauss, Jo Waaler
Journal: Cancer Research (2022)

Abstract The catalytic enzymes tankyrase 1 and 2 (TNKS1/2) poly-ADP-ribosylate target proteins, including AXIN proteins, to earmark them for degradation by the ubiquitin-proteasomal system. Hence, inhibition of TNKS1/2 can stabilize AXIN proteins, and consequently β-catenin degradosomes, resulting in inhibition of WNT/β-catenin signaling. Although several potent small-molecules have been developed to inhibit TNKS1/2 and oncogenic WNT/β-catenin signaling, also showing convincing anti-tumor effects in numerous mouse cancer models, there are currently no TNKS1/2 inhibitors available in the clinic. The development has mainly been disadvantaged by concerns over previous reports unfolding intestinal toxicity, apparently caused by on-target and WNT/β-catenin signaling pathway-specific side effects, and a deficient therapeutic index. Here we show that the novel, highly potent and selective1,2,4-triazole-based TNKS1/2 inhibitor OM-153, displaying improved ADME-properties and mouse pharmacokinetics, reduced WNT/β-catenin signaling and tumor progression in COLO 320DM colon cancer xenografts upon peroral (PO) administration of 0.33-10 mg/kg twice daily (BID). In addition, combined OM-153 and anti-PD-1 treatment conferred a synergistic anti-tumor effect in a B16-F10 mouse melanoma model. In a 28-day repeated dose mouse toxicity study, body weight loss, intestinal damage and tubular damage in the kidney was documented after PO BID administration of 100 mg/kg. In contrast, in mice treated PO BID using 10 mg/kg, the intestinal architecture was intact and no atypical histopathological changes were observed in other organs, while clinical biochemistry and haematological analyses did not identify any changes indicating considerable toxicity. The results provide a scaffold for using OM-153 as a potential anti-cancer treatment and additional preclinical and clinical evaluations. Citation Format: Shoshy Alam Brinch, Enya Amundsen-Isaksen, Sandra Espada, Aleksandra Aizenshtadt, Lone Holmen, Clara Hammarström, Merete Høyem, Hanne Scholz, Gunnveig Grødeland, Sven T. Sowa, Albert Galera-Prat, Lari Lehtiö, Ilonka A.T.M. Meerts, Ruben G. G. Leenders, Anita Wegert, Stefan Krauss, Jo Waaler. The tankyrase inhibitor OM-153 demonstrates anti-tumor effect with a therapeutic index above 10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2651.
Glucosamine amends CNS pathology in mucopolysaccharidosis IIIC mouse expressing misfolded HGSNAT
Authors: Xuefang Pan, Mahsa Taherzadeh, Poulomee Bose, Rachel Heon-Roberts, Annie L.A. Nguyen, TianMeng Xu, Camila Pará, Yojiro Yamanaka, David A. Priestman, Frances M. Platt, Shaukat Khan, Nidhi Fnu, Shunji Tomatsu, Carlos R. Morales, Alexey V. Pshezhetsky
Journal: The Journal of Experimental Medicine (2022)

The majority of mucopolysaccharidosis IIIC (MPS IIIC) patients have missense variants causing misfolding of heparan sulfate acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), which are potentially treatable with pharmacological chaperones. To test this approach, we generated a novel HgsnatP304L mouse model expressing misfolded HGSNAT Pro304Leu variant. HgsnatP304L mice present deficits in short-term and working/spatial memory 2-4 mo earlier than previously described constitutive knockout Hgsnat-Geo mice. HgsnatP304L mice also show augmented severity of neuroimmune response, synaptic deficits, and neuronal storage of misfolded proteins and gangliosides compared with Hgsnat-Geo mice. Expression of misfolded human Pro311Leu HGSNAT protein in cultured hippocampal Hgsnat-Geo neurons further reduced levels of synaptic proteins. Memory deficits and majority of brain pathology were rescued in mice receiving HGSNAT chaperone, glucosamine. Our data for the first time demonstrate dominant-negative effects of misfolded HGSNAT Pro304Leu variant and show that they are treatable by oral administration of glucosamine. This suggests that patients affected with mutations preventing normal folding of the enzyme can benefit from chaperone therapy.
Abstract 788: <i>Prrx1</i> regulates acinar cell plasticity in <i>Kras</i>-driven pancreatic acinar-to-ductal metaplasia
Authors: Alina L. Li, Kensuke Sugiura, Kensuke Suzuki, Jason R. Pitarresi, Anna M. Chiarella, Gizem Efe, Rohit Chandwani, Anil K. Rustgi
Journal: Cancer Research (2022)

Abstract Introduction: Acinar cells in the adult pancreas demonstrate cellular plasticity and undergo de-differentiation to a progenitor-like cell type with ductal characteristics after injury. This process, termed acinar-to-ductal metaplasia (ADM), is an important feature facilitating pancreas regeneration after injury. In the absence of oncogenic mutations, the ADM lesions resolve and reform the acinar compartment (adaptive ADM). However, in the presence of oncogenic Kras mutations (oncogenic ADM), acinar cells undergo neoplastic transformation after ADM and evolve to pancreatic intraepithelial neoplasia (PanIN), a well-known precursor of pancreatic ductal adenocarcinoma (PDAC). We have characterized the role of Paired-Related Homeobox1 (PRRX1) in adaptive ADM. We demonstrated through our novel conditional Prrx1 knock-out mouse model that loss of Prrx1 abrogated ADM formation. Here we explore the relationship between Prrx1 and mutant Kras on promoting ADM and a pro-ADM microenvironment. Methods: We generated novel Pdx1-Cre;LSLKrasG12D/+;Prrx1fl/fl;Rosa26YFP/YFP (KCY Prrx1 KO) mice, in which mutant Kras is efficiently expressed and Prrx1 is deleted in a pancreas-specific manner. KCY Prrx1 WT and KO mice were sacrificed at 3 months and 5 months for histological analysis. Immunofluorescence (IF) staining for CK19, characterized for the rate of ADM formation and evaluated for F4/80 and SMA. Quantification of ADM regions, F4/80 and SMA was performed through automated cell-counting of immunofluorescence staining (IF). Dissociated acinar cell culture in collagen was utilized for the evaluation of ADM under ex vivo conditions. Results: IF staining revealed that KCY Prrx1 KO mice had fewer ADM lesions compared to Prrx1 WT mice at 3 months. This difference became dramatically apparent at the 5 month timepoint. Additionally, lower areas of fibrosis were identified via H&amp;E staining in KCY Prrx1 KO mice, which was accompanied with lower F4/80 and SMA positivity at both 3 months and 5 months. Ex vivo cultures also demonstrated significant reduction in ADM formation in the context of oncogenic Kras and loss of Prrx1. Conclusions: PRRX1 can influence ADM formation in both a cell-intrinsic and cell-extrinsic manner in the presence of oncogenic KRAS. Our preliminary data suggest Prrx1 facilitates PDAC progression through PanIN formation. We will continue to investigate the mechanisms driving Prrx1-dependent ADM formation. Citation Format: Alina L. Li, Kensuke Sugiura, Kensuke Suzuki, Jason R. Pitarresi, Anna M. Chiarella, Gizem Efe, Rohit Chandwani, Anil K. Rustgi. Prrx1 regulates acinar cell plasticity in Kras-driven pancreatic acinar-to-ductal metaplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 788.
Abstract 1783: JNK/MDR1 confers chemo-resistance in breast cancer cells carrying estrogen receptor activating mutations
Authors: Marwa Taya, Keren Merenbakh-Lamin, Tami Rubinek, Ido Wolf
Journal: Cancer Research (2022)

Abstract Background: Endocrine therapy is the mainstay treatment for estrogen receptor-α (ER) positive breast cancer (BC) patients. However, all metastatic BC patients develop resistance, which in nearly 40% of patients is due to activating mutations, mostly Y537S and D538G, in the ligand-binding domain (LBD). Tumors harboring these mutations are more aggressive and the patients' prognosis is worse. We hypothesized that refractory response to further treatment lines, i.e, chemotherapy, partially accounts for the worse prognosis. Hence, our goal was to study whether LBD-ER BC cells are resistant to chemotherapy and reveal the mechanism of action. Methods: We used MCF-7 cells stably expressing WT-ER, Y537S or D538G-ER mutations. Cell proliferation and viability were determined using MTT, methylene blue and colony assays. We evaluated apoptosis by monitoring cleaved-PARP and flow cytometry using Annexin/7AAD staining. MDR1 expression was studied using qRT-PCR and western-blot. JNK/c-Jun pathway was studied by pJNK and cJun expressions, cJun transcriptional activity, ChIP assay and pharmacological inhibition. Results: LBD-ER cells exhibited higher proliferation and viability and exerted less apoptosis compared to WT-ER cells following treatment with paclitaxel, doxorubicin, and 5-FU. MDR1 expression and JNK pathway activity was higher in D538G cells compared to both WT-ER and Y537S cells. Importantly, inhibition of the JNK pathway, using SP600125 and BI-78D3, lead to decreased MDR1 expression, increased cleaved PARP, and decreased viability in the D538G cells. In addition, our results revealed that JNK increased c-Jun binding activity of the MDR1 gene in the D538G mutated cells. Conclusions: These results indicate that LBD-ER cells confer resistance to chemotherapy. The mechanisms leading to it are diverse, and we found that in D538G increased JNK pathway activation resulted in elevated MDR1 expression and chemo-resistance. This paves the way to therapies aiming at inhibition the JNK pathway in order to restore chemo-resistance. This study also highlights the marked differences between these seemingly similar mutations, strengthening the necessity to adopt a personalized treatment approach for BC patients who developed endocrine resistance. Citation Format: Marwa Taya, Keren Merenbakh-Lamin, Tami Rubinek, Ido Wolf. JNK/MDR1 confers chemo-resistance in breast cancer cells carrying estrogen receptor activating mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1783.